PMID: 

J Agric Food Chem. 2020 Jan 22 ;68(3):759-768. Epub 2019 Dec 31. PMID: 31841328

Abstract Title: 

Antihypertensive Effects in Vitro and in Vivo of Novel Angiotensin-Converting Enzyme Inhibitory Peptides from Bovine Bone Gelatin Hydrolysate.

Abstract: 

In this study, we investigated the antihypertensive effectsandof novel angiotensin-converting enzyme inhibitory (ACEI) peptides purified and identified from bovine bone gelatin hydrolysate (BGH). Thirteen ACEI peptides were identified from BGH, and among which, RGL-(Hyp)-GL and RGM-(Hyp)-GF exhibited high ACE inhibition with ICvalues of 1.44 and 10.23μM. Molecular docking predicted that RGM-(Hyp)-GF and ACE residues of Glu384, His513, and Lys511 formed hydrogen-bonding interactions at distances of 2.57, 2.99, and 2.42 + 3.0 Å. RGL-(Hyp)-GL formed hydrogen bonds with Lys511 and Tyr523 and generated hydrogen-bonding interactions with His387 andGlu411 in the zinc(II) complexation motif at distances of 2.74 and 3.03 + 1.93 Å. The maximal decrements in systolic blood pressure in spontaneously hypertensive rats induced by one-time gavage of RGL-(Hyp)-GL and RGM-(Hyp)-GF at 30 mg/kg were 31.3 and 38.6 mmHg. RGL-(Hyp)-GL had higher enzyme degradation resistance than that of RGM-(Hyp)-GFincubation in rat plasma, and they were sequentially degraded into pentapeptides and tetrapeptides within 2 h. Our results indicate that BGH can serve as a nutritional candidate to control blood pressure.

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PMID: 

Front Microbiol. 2019 ;10:2643. Epub 2019 Nov 28. PMID: 31849852

Abstract Title: 

Novel Angiotensin-Converting Enzyme-Inhibitory Peptides From Fermented Bovine Milk Started byKLDS.31 andKLDS.105: Purification, Identification, and Interaction Mechanisms.

Abstract: 

Fermented milks with strong angiotensin I-converting enzyme (ACE)-inhibitory activity were obtained through a culture withKLDS.31 andKLDS.105 with a fermentation and storage temperature of 37°C. Ultrafiltration fractions with a molecular weight less than 3 kDa in fermented milk whey exhibited the strongest inhibitory activity. Correspondingly, a gastrointestinal digestion experiment showed retention of the bioactivity of these fractions with pepsin and trypsin treatment. Four ACE-inhibitory peptides from fermented milk were isolated, purified by two-step reverse chromatography, and sequenced. Furthermore, the interaction mechanisms between ACE and four isolated peptides were investigated by a molecular docking method and the Independent Gradient Model. Experimental determinationof ICwas done to verify theoretical results. The inhibitory peptide interacted with ACE as follows: Lys-Pro-Ala-Gly-Asp-Phe>Lys-Ala-Ala-Leu-Ser-Gly-Met>Lys-Lys-Ala-Ala-Met-Ala-Met>Leu-Asp-His-Val-Pro-Gly-Gly-Ala-Arg.

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PMID: 

Foods. 2020 Jan 8 ;9(1). Epub 2020 Jan 8. PMID: 31936191

Abstract Title: 

Whey Protein Concentrate as a Novel Source of Bifunctional Peptides with Angiotensin-I Converting Enzyme Inhibitory and Antioxidant Properties: RSM Study.

Abstract: 

Whey protein concentrate (WPC) is a unique source of protein with numerous nutritional and functional values due to the high content of branched-chain amino acid. This study was designed to establish the optimum conditions for Alcalase-hydrolysis of WPC to produce protein hydrolysates with dual biofunctionalities of angiotensin-I converting enzyme (ACE) inhibitory and antioxidant activities via response surface methodology (RSM). The results showed that the optimum conditions were achieved at temperature = 58.2°C, E/S ratio = 2.5%, pH = 7.5 and hydrolysis time = 361.8 min in order to obtain the maximum DH (89.2%), ACE-inhibition (98.4%), DPPH• radical scavenging activity (50.1%) and ferrous ion chelation (73.1%). The well-fitted experimental data to predicted data further validates the regression modeladequacy. Current study demonstrates the potential of WPC to generate bifunctional hydrolysates with ACE inhibition and antioxidant activity. This finding fosters the use of WPC hydrolysate as a novel, natural ingredient for the development of functional food products.

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PMID: 

Int J Mol Sci. 2020 Feb 25 ;21(5). Epub 2020 Feb 25. PMID: 32106617

Abstract Title: 

Antioxidant Blueberry Anthocyanins Induce Vasodilation via PI3K/Akt Signaling Pathway in High-Glucose-Induced Human Umbilical Vein Endothelial Cells.

Abstract: 

Blueberries are rich in antioxidant anthocyanins. The hypotensive effects of blueberry anthocyanins in endothelial cells was investigated here. Pretreatment with blueberry anthocyanin extract, malvidin, malvidin-3-glucoside, and malvidin-3-galactoside significantly ameliorated high-glucose-induced damage by enhancing endogenous antioxidant superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), lowering reactive oxygen species (ROS) generation and NADPH oxidase isoform 4 (NOX4) expression, and increasing the cell vitalities. They also effectively induced a vasodilatory effect by increasing the vasodilator nitric oxide (NO) and its promoters endothelial NO synthase (eNOS) and peroxisome proliferator-activated receptor-γ (PPARγ) levels as well as by decreasing the vasoconstrictor angiotensin-converting enzyme (ACE), xanthine oxidase-1 (XO-1), and low-density lipoprotein (LDL) levels. The activation of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and the breakdown of protein kinase C zeta (PKCζ) pathway were involved in the bioactivities. The results indicated blueberry anthocyanins protected endothelial function against high-glucose (HG) injury via antioxidant and vasodilatory mechanisms, which could be promising molecules as a hypotensive nutraceutical for diabetes patients.

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PMID: 

J Ethnopharmacol. 2020 Feb 28:112724. Epub 2020 Feb 28. PMID: 32119952

Abstract Title: 

Anti-hypertensive and angiotensin-converting enzyme inhibitory effects of Radix Astragali and its bioactive peptide AM-1.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Hypertension is one of the common chronic health problems in the world. Astragalus membranaceus root (AM), also known as Huangqi, is a popular medicinal herb traditionally used to reinforce vital energy and modulate hypertension.AIM OF THE STUDY: This study was to reveal the anti-hypertensive activities and mechanisms of AM in spontaneously hypertensive rats (SHRs). Moreover, the presence of bioactive components in AM was further identified.MATERIALS AND METHODS: We analyzed the effects of aqueous extract of AM (AME) on the regulation of blood pressure and angiotensin converting enzyme (ACE), the major target of anti-hypertensive drugs. Proteomic, bioinformatics, and docking analyses were performed to identify the anti-hypertensive bioactive peptides in AME.RESULTS: Our data showed that AME inhibited ACE activities in a dose-dependent manner, with an ICof 1.85 ± 0.01 μg/ml. In comparison with mock, oral administration of AME reduced systolic blood pressure (SBP) levels in SHRs, and the level of SBP was decreased by 22.33 ± 3.61 mmHg at 200 mg/kg AME. Proteomic analysis identified that an abundant 152-amino-acid putative protein kinasefragment accounted for approximately 11.7% of protein spots in AME. AM-1 (LVPPHA), a gastrointestinal enzyme-resistant peptide cleaved from putative protein kinase fragment, inhibited ACE activities, with an ICvalue of 414.88 ± 41.88 μM. Moreover, oral administration of AM-1 significantly decreased SBP levels by 42 ± 2.65 mmHg at 10 μmol/kg. Docking analysis further showed that AM-1 docked into the active site channel of ACE and interacted with Ala-354 in the active site pocket of ACE.CONCLUSIONS: the ACE inhibitory effect of AM and the presence of ACE inhibitory phytopeptide in AME supported the ethnomedical use of AM on hypertension.

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PMID: 

Nutrients. 2018 Nov 12 ;10(11). Epub 2018 Nov 12. PMID: 30424556

Abstract Title: 

Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney.

Abstract: 

The renin-angiotensin system (RAS), especially the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) axis, plays an important role in the aging process of the kidney, through increased tissue reactive oxygen species production and progressively increased oxidative stress. In contrast, the angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis, which counteracts the effects of Ang II, is protective for end-organ damage. To evaluate the ability of resveratrol (RSV) to modulate the RAS in aging kidneys, eighteen-month-old male C57BL/6 mice were divided into two groups that received either normal mouse chow or chow containing resveratrol, for six months. Renal expressions of RAS components, as well as pro- and antioxidant enzymes, were measured and mouse kidneys were isolated for histopathology. Resveratrol-treated mice demonstrated better renal function and reduced albuminuria, with improved renal histologic findings. Resveratrol suppressed the Ang II/AT1R axis and enhanced the AT2R/Ang 1-7/MasR axis. Additionally, the expression of nicotinamide adenine dinucleotide phosphate oxidase 4, 8-hydroxy-2'-deoxyguanosine, 3-nitrotyrosine, collagen IV, and fibronectin was decreased, while the expression of endothelial nitric oxide synthase and superoxide dismutase 2 was increased by resveratrol treatment. These findings demonstrate that resveratrol exerts protective effects on aging kidneys by reducing oxidative stress, inflammation, and fibrosis, through Ang II suppression and MasR activation.

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PMID: 

Am J Physiol Endocrinol Metab. 2007 May ;292(5):E1378-87. Epub 2007 Jan 16. PMID: 17227956

Abstract Title: 

EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR.

Abstract: 

Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 microM) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg.kg(-1).day(-1)), enalapril (30 mg.kg(-1).day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome.

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PMID: 

Biosci Biotechnol Biochem. 2007 Aug ;71(8):2079-82. Epub 2007 Aug 7. PMID: 17690452

Abstract Title: 

Dietary supplementation with epigallocatechin gallate elevates levels of circulating adiponectin in non-obese type-2 diabetic Goto-Kakizaki rats.

Abstract: 

Epigallocatechin gallate (EGCG) reportedly enhances plasma adiponectin levels in models of insulin resistance and obesity. In this study, we found that EGCG increases plasma adiponectin levels and decreases plasma triacylglycerol levels in non-obese diabetic Goto-Kakizaki rats with insulin secretory dysfunction. These results suggest that EGCG ameliorates lipid metabolic abnormality even in non-obese rats, probably by increasing adiponectin production.

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PMID: 

J Nutr Sci Vitaminol (Tokyo). 2007 Dec ;53(6):496-500. PMID: 18202537

Abstract Title: 

Effects of dietary catechins on glucose tolerance, blood pressure and oxidative status in Goto-Kakizaki rats.

Abstract: 

Effects of green tea catechins comprising EGCg, EGC, ECg, EC, GCg, GC, Cg, and C were determined on blood glucose tolerance and oxidative stress status in type 2 diabetic Goto-Kakizaki (GK) rats. GK rats fed the catechin-containing diet tended to maintain blood glucose and systolic blood pressure at lower levels in the latter stages of the feeding period of 76 d, compared to those not receiving dietary catechins (control group). The blood glucose tolerance test performed on days 48-49 showed that GK rats fed the catechins had lower blood glucose levels than GK rats not fed catechins during the 120 min after glucose loading. In catechin-fed rats, amounts of 8-OH dG and albumin excreted into the urine determined on days 71-72, and kidney ACE activity determined on day 76, were lower than those in control rats. From these results it is concluded that dietary catechins may be effective in delaying the progression of diabetes and the associated oxidative stress.

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PMID: 

Oncotarget. 2018 Jan 26 ;9(7):7411-7423. Epub 2017 Dec 21. PMID: 29484120

Abstract Title: 

Epigallocatechin-3-gallate suppresses differentiation of adipocytes via regulating the phosphorylation of FOXO1 mediated by PI3K-AKT signaling in 3T3-L1 cells.

Abstract: 

Epigallocatechin-3-gallate (EGCG) is a pivotal effective component of green tea. It is known that EGCG has antioxidant activity, anti-angiogenesis, anti-tumor, cardiovascular protection and blood lipid regulation functions. Forkhead box-O1 (FOXO1) is one of the downstream signals of protein kinase B (AKT) and takes part in adipogenesis. The purpose of this study is to investigate the effects of EGCG on adipose differentiation and the likely mechanisms. 3T3-L1 cells were induced by DMI for 2, 4, 6 and 8 days, respectively. During induction, the cells were treated with EGCG (5μM, 10 μM, 50 μM and 100 μM) or DMSO for the first 2 days. In addition, another batch of 3T3-L1cells were treated with SC-3036 (PI3K activator, 10 µM), or LY294002 (PI3K inhibitor, 10 µM) alone or combined with EGCG (100 μM) for the indicated times. Medium glucose concentration, lipid accumulation, the levels of TNF-α, resistin, adiponectin and leptin and the expression of FOXO1, phosphorylated-FOXO1 (P-FOXO1), PPARγ, fatty acid synthase (FAS) were detected, respectively. The present study demonstrated that EGCG inhibited glucose uptake, lipid accumulation and adipokine secretion in aconcentration-dependent manner during adipogenesis, which suggests that EGCG inhibits adipocyte's differentiation, maturation and functions. Moreover, EGCG also down-regulated the expression levels of PPARγ and P-FOXO1. Conversely, the PI3K activator reversed these changes caused by EGCG, suggesting that the inhibitory effects of EGCG may be mediated by PI3K-AKT-FOXO1 pathway to negatively regulate the expression of PPARγ. The findings will provide a solid foundation for EGCG to prevent and cure the obesity-associated diseases.

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